Major depression represents one of the most common mental illnesses, affecting between 5-10% of the population. The disease is characterized by extreme changes in mood which may also be associated with psychoses. It has generally been found that most antidepressant agents exert significant effects on the regulation of monoamine neurotransmitters. The tricyclic antidepressants, such as imipramine, are the most commonly used drugs for the treatment of depression. Their ability to inhibit the neuronal uptake of norepinephrine is believed to be a major factor behind their efficacy.
A number of new types of antidepressants have been developed in recent years. Two compounds that are currently marketed in the United States are trazodone and fluoxetine. Both of these compounds interact with the regulation of 5-HT. Trazodone controls the actions of 5-HT while fluoxetine is a potent and selective inhibitor of 5-HT reuptake. 3-Chloroimipramine which inhibits both 5-HT and norepinephrine reuptake has been extensively used as an antidepressant in Europe and Canada. Other compounds which are of current interest or have been examined as antidepressants include fluvoxamine, citalopram, zimeldine, sertraline, bupropion and nomifensine. All of these drugs inhibit monamine uptake mechanisms, but differ in selectivity between the dopamine, 5-HT and norepinephrine transporters.
Considerable attention has recently been directed to the condition known as attention-deficit hyperactivity disorder. Children with this condition tend to be very active physically but have great difficulty with situations requiring long periods of attention. Consequently, they tend to underachieve academically and can be very disruptive. Furthermore, these behavioral problems often persist in modified forms into adulthood. The condition appears to be associated with the effect of monoamines in the cerebral cortex, which are involved with control of attention. A number of stimulant drugs such as dextroamphetamine, methylphenidate as well as the tricyclic antidepressants, antipsychotic agents and clonidine have been used as medications to control the disorder. Many of these drugs interact with the monoamine uptake transporters.
Cocaine addiction represents a major societal problem. The development of compounds that can modify the biological actions of cocaine would be very beneficial for the treatment of cocaine addiction. Cocaine is an inhibitor of both the dopamine and serotonin transporter, and so potent and selective compounds for this transporter can modify the biological consequences of cocaine.
Development of radiopharmaceuticals for the functional brain imaging has progressed rapidly in recent years. Both position emission tomography (PET) and single photon emission computed tomography (SPECT) ligands are now successfully employed for the study of receptors of the central nerve system (CNS) including ligands for the dopamine, muscarenic, opiate and benzodiazepine receptors. In particular, a large number of dopamine transporter imaging agents based on cocaine or tropane derivatives, have been reported. Although a large number of tropane derivatives have been developed into the radiolabeled ligands for the dopamine transporters, there are very few radiolabeled ligands available for the serotonin transporters. (Kung, H. F., et al. J. Nucl. Med. 1994, 35, 93p.; Mathis, C. A., et al., J. Labelled compd. Radiopharm. 1994, 34, 905), and no radioligand is available for the serotonin transporters based on tropane derivatives.
It has previously been shown that cocaine and related compounds are potent inhibitors of dopamine reuptake and this leads to compounds with reinforcing properties. In recent years a number of new extremely potent cocaine analogs have been prepared based on the tropane structure (Abraham et al., Journal of Medicinal Chemistry 1992, 35, 141; Boja et al., European Journal of Pharmacology, 1990, 183, 329; Boja et al., European Journal of Pharmacology, 1991, 194, 133; Carroll et al., Journal of Medicinal Chemistry, 1992, 35, 969; Carroll et al., Journal of Medicinal Chemistry, 1992, 35, 1813; Carroll et al., Journal of Medicinal Chemistry, 1992, 35, 2497, Cline et al., Journal of Pharmacology and Experimental Therapeutics, 1992, 260, 1174; Cline et al., Synapse, 1992, 12, 37; Kozikowski et al., Medicinal Chemistry Research, 1991, 1, 312; Kosikowski et al., Journal of Medicinal Chemistry, 1992, 35, 4764; Lewin et al., Journal of Medicinal Chemistry, 1992, 35, 135; Madras et al., Molecular Pharmacology, 1989, 36, 518, Carroll, F. I., et al., J. Chem. Soc., Chem. Commun. 1993, 44-46; Carroll, F. I. et al., J. Med. Chem. 1995, 38, 379; Carroll, F. I. et al., J. Med. Chem. 1993, 36, 2886; Carroll et al. J. Med. Chem. 1994, 37, 2865; Meltzer, P. C., et al. J. Med. Chem. 1993, 36, 855-862; Carroll, F. I., et al. J. Med. Chem. 1995, 38, 379-388; Boja, J. W., et al. J. Med. Chem. 1994, 37, 1220-1223; Carroll, F. I., et al. J. Med. Chem. 1994, 37, 2865; Kozikowski, A. P., et al. Biorg. Med. Chem. Lett. 1993, 3, 1327-1332; Simoni, D. et al., J. Med. Chem. 1993, 36, 3975-3977; Kozikowski, A. P., et al. J. Med. Chem. 1995, 38, 3086-3093; Kozikowski, A. P., et al. J. Med. Chem. 1994, 37, 3440-3442; Meltzer, P. C. et al., J. Med. Chem. 1994, 37, 2001-2010; Madras, B. K., et al. Synapse 1996, 24, 340-348; Chen, Z., et al., Tetrahedron Lett. 1997, 38, 1121-1124; Kelkar, S. V. et al., J. Med. Chem. 1994, 37, 3875-3877; Chen, Z., et al. J. Med. Chem. 1996, 39, 4744-4749; Xu, L. et al. J. Med. Chem. 1997, 40, 858-863; Moldt et al., U.S. Pat. No. 5,369,113, issued Nov. 29, 1994; Moldt et al., U.S. Pat. No. 5,374,636, issued Dec. 20, 1994; Kozikowski, U.S. Pat. No. 5,391,744, issued Feb. 21, 1995; Kuhar, et al., U.S. Pat. No. 5,380,848, issued Jan. 10, 1995; Carroll, et al., U.S. Pat. No. 5,128,118, issued Jul. 7, 1992; Kozikowski, U.S. Pat. No. 5,268,480, issued Dec. 7, 1993). All of these compounds are based on the tropane skeleton. These compounds tend to selectively bind to the dopamine transporter and certain structural variations can lead to compounds that bind with very high selectivity to the dopamine reuptake site (Carroll et al., J. Med. Chem., 1992, 35, 2497). Only a few tropane derivatives have been prepared that exhibit a preference for binding to the 5-HT transporter over the dopamine transporter (Boja, J. W., et al., J. Med. Chem. 1994, 37, 1220; Blough, B. E., et al., J. Med. Chem. 1996, 39, 4027-4035; Davies, H. M. L., et al., J. Med. Chem. 1996, 39, 2554; Blough, B. E. et al., J. Med. Chem., 1997, 40, 3861-3864). All of these tropane derivatives are very similar to each other because they are all derived from cocaine as starting material.
In principle, the tropane skeleton is ideally suited to prepare highly selective compounds because it is a rigid structure and so derivatives will have rather limited conformational flexibility. It would therefore be very valuable if the binding selectivity of the tropane skeleton could be altered by appropriate structural changes so that analogs favoring binding to the 5-HT reuptake site could be prepared. In a previous Davies, et al. patent application filed Jan. 22, 1996, Ser. No. 08/589,820 now U.S. Pat. No. 5,760,055, and entitled Biologically Active Tropane Derivatives, which application is incorporated herein by reference, it is taught how the novel chemistry that was there developed has enabled preparation of a much wider range of tropane analogs than was previously accessible, leading to novel structures with moderate potency and improved selectivity for the 5-HT transporter (Davies, H. M. L., et al. Eur. J. Pharmacol. 1993, 244, 93; Davies, H. M. L. et al., J. Med. Chem. 1994, 37, 1262; Bennett, B. A. et al., J. Pharmacol. Exp. Ther. 1995, 272, 1176). The work that formed the basis of the previous incorporated by reference U.S. patent application has appeared as a published article (Davies, H. M. L. et al. J. Med. Chem. 1996, 39, 2554).
It has now been discovered that if the tropane system is modified, particularly at the aryl moiety as hereinafter described, compounds can be produced that are over 800 times more potent at the 5-HT transporter compared to the dopamine transporter and have much lower binding affinities to the norepinephrine than those that were described in the prior referred to U.S. Patent application (see examples 1 and 2 below). Since these tropanes (as described below) bind preferentially to the 5-HT transporter, they may preferentially block 5-UT transport, thus increasing synaptic levels of 5-HT. This should be helpful in treating diseases related to 5-HT function. Furthermore, many of the tropanes are iodinated compounds or the alkyltin precursors to the iodinated compounds. The high binding affinities and 5-HT selectivities of these iodinated compounds mean that the [I-125]-derivatives and others may be useful as diagnostic agents for the treatment of depression.
Accordingly, it is a primary objective of the present invention to provide a process for development of new tropane analogs which bind selectively to the 5-HT transporter.
Another primary objective of the present invention is to prepare a series of tropane analogs which are candidates for treatment of chronic depression.
A still further primary objective of the present invention is to prepare a series of tropane analogs which are candidates for the treatment of cocaine addiction.
Another objective of the present invention is to prepare a series of tropane analogs that are iodinated compounds or the alkyltin precursors to the iodinated compounds, whose [I123} derivatives should be 5-HT selective SPECT (single photon emission computed tomography) diagnostic agents for depression.
An even further objective of the present invention is to provide a wide range of tropane derivatives which can be systematically used and tested to determine structure-activity relationships for binding at dopamine, 5-HT and norepinephrine transporters.
The method and manner of accomplishing each of the above objectives as well as others will become apparent from the description of the invention that follows. It is understood that modifications may be made to the steps of the synthesis and to the compounds prepared without departing from the spirit and scope of the invention, as long as the compounds which are prepared selectively bind to the serotonin reuptake transporters.